CN110642766B - Monoamine oxidase A inhibitor - Google Patents
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- CN110642766B CN110642766B CN201910818696.1A CN201910818696A CN110642766B CN 110642766 B CN110642766 B CN 110642766B CN 201910818696 A CN201910818696 A CN 201910818696A CN 110642766 B CN110642766 B CN 110642766B
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- 229940091512 Monoamine oxidase A inhibitor Drugs 0.000 title claims abstract description 18
- 238000006243 chemical reaction Methods 0.000 claims abstract description 33
- 102000010909 Monoamine Oxidase Human genes 0.000 claims abstract description 21
- 108010062431 Monoamine oxidase Proteins 0.000 claims abstract description 21
- 150000001875 compounds Chemical class 0.000 claims abstract description 21
- 238000000034 method Methods 0.000 claims abstract description 17
- 230000000694 effects Effects 0.000 claims abstract description 12
- 238000002360 preparation method Methods 0.000 claims abstract description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 12
- 230000002401 inhibitory effect Effects 0.000 claims abstract description 11
- 239000002904 solvent Substances 0.000 claims abstract description 9
- KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical compound [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 claims abstract description 7
- 230000001590 oxidative effect Effects 0.000 claims abstract description 7
- 239000003054 catalyst Substances 0.000 claims abstract description 6
- 239000003814 drug Substances 0.000 claims abstract description 6
- 239000007800 oxidant agent Substances 0.000 claims abstract description 4
- 241000872931 Myoporum sandwicense Species 0.000 claims abstract description 3
- 239000002994 raw material Substances 0.000 claims abstract description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 12
- 239000000126 substance Substances 0.000 claims description 11
- 238000005406 washing Methods 0.000 claims description 5
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 4
- 239000000706 filtrate Substances 0.000 claims description 4
- 239000000047 product Substances 0.000 claims description 4
- 238000001704 evaporation Methods 0.000 claims description 3
- 230000008020 evaporation Effects 0.000 claims description 2
- JQWHASGSAFIOCM-UHFFFAOYSA-M sodium periodate Chemical compound [Na+].[O-]I(=O)(=O)=O JQWHASGSAFIOCM-UHFFFAOYSA-M 0.000 abstract description 8
- -1 sulfone compound Chemical class 0.000 abstract description 6
- 230000005764 inhibitory process Effects 0.000 abstract description 5
- NCPHGZWGGANCAY-UHFFFAOYSA-N methane;ruthenium Chemical compound C.[Ru] NCPHGZWGGANCAY-UHFFFAOYSA-N 0.000 abstract description 5
- 229910001927 ruthenium tetroxide Inorganic materials 0.000 abstract description 5
- 150000003568 thioethers Chemical class 0.000 abstract description 5
- 229940079593 drug Drugs 0.000 abstract description 4
- 201000010099 disease Diseases 0.000 abstract description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 3
- 238000003786 synthesis reaction Methods 0.000 abstract description 3
- 230000015572 biosynthetic process Effects 0.000 abstract description 2
- 239000000243 solution Substances 0.000 description 9
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 8
- 239000000523 sample Substances 0.000 description 8
- 239000003112 inhibitor Substances 0.000 description 6
- 102000004190 Enzymes Human genes 0.000 description 5
- 108090000790 Enzymes Proteins 0.000 description 5
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 description 2
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 208000018737 Parkinson disease Diseases 0.000 description 2
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 description 2
- 239000004327 boric acid Substances 0.000 description 2
- 239000000872 buffer Substances 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- 238000007254 oxidation reaction Methods 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- MPDDTAJMJCESGV-CTUHWIOQSA-M (3r,5r)-7-[2-(4-fluorophenyl)-5-[methyl-[(1r)-1-phenylethyl]carbamoyl]-4-propan-2-ylpyrazol-3-yl]-3,5-dihydroxyheptanoate Chemical compound C1([C@@H](C)N(C)C(=O)C2=NN(C(CC[C@@H](O)C[C@@H](O)CC([O-])=O)=C2C(C)C)C=2C=CC(F)=CC=2)=CC=CC=C1 MPDDTAJMJCESGV-CTUHWIOQSA-M 0.000 description 1
- LKJPYSCBVHEWIU-KRWDZBQOSA-N (R)-bicalutamide Chemical compound C([C@@](O)(C)C(=O)NC=1C=C(C(C#N)=CC=1)C(F)(F)F)S(=O)(=O)C1=CC=C(F)C=C1 LKJPYSCBVHEWIU-KRWDZBQOSA-N 0.000 description 1
- KEJXHTBYIHTFHA-UHFFFAOYSA-N 7-(3-aminopropoxy)-4-methylchromen-2-one Chemical compound C1=C(OCCCN)C=CC2=C1OC(=O)C=C2C KEJXHTBYIHTFHA-UHFFFAOYSA-N 0.000 description 1
- 208000024827 Alzheimer disease Diseases 0.000 description 1
- 206010005003 Bladder cancer Diseases 0.000 description 1
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- 206010008342 Cervix carcinoma Diseases 0.000 description 1
- MQJKPEGWNLWLTK-UHFFFAOYSA-N Dapsone Chemical compound C1=CC(N)=CC=C1S(=O)(=O)C1=CC=C(N)C=C1 MQJKPEGWNLWLTK-UHFFFAOYSA-N 0.000 description 1
- 208000000461 Esophageal Neoplasms Diseases 0.000 description 1
- 206010024229 Leprosy Diseases 0.000 description 1
- 206010049287 Lipodystrophy acquired Diseases 0.000 description 1
- 239000005578 Mesotrione Substances 0.000 description 1
- 229940123685 Monoamine oxidase inhibitor Drugs 0.000 description 1
- 206010030155 Oesophageal carcinoma Diseases 0.000 description 1
- 102000004005 Prostaglandin-endoperoxide synthases Human genes 0.000 description 1
- 108090000459 Prostaglandin-endoperoxide synthases Proteins 0.000 description 1
- 206010060862 Prostate cancer Diseases 0.000 description 1
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 1
- 229940124639 Selective inhibitor Drugs 0.000 description 1
- 206010039966 Senile dementia Diseases 0.000 description 1
- UCKMPCXJQFINFW-UHFFFAOYSA-N Sulphide Chemical compound [S-2] UCKMPCXJQFINFW-UHFFFAOYSA-N 0.000 description 1
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 description 1
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 description 1
- 230000032683 aging Effects 0.000 description 1
- 239000003905 agrochemical Substances 0.000 description 1
- 230000002280 anti-androgenic effect Effects 0.000 description 1
- 239000000051 antiandrogen Substances 0.000 description 1
- 206010003246 arthritis Diseases 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 229960000997 bicalutamide Drugs 0.000 description 1
- 229940098773 bovine serum albumin Drugs 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- 239000002327 cardiovascular agent Substances 0.000 description 1
- 229940125692 cardiovascular agent Drugs 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 201000010881 cervical cancer Diseases 0.000 description 1
- 201000010989 colorectal carcinoma Diseases 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 239000010779 crude oil Substances 0.000 description 1
- 229960000860 dapsone Drugs 0.000 description 1
- 238000006477 desulfuration reaction Methods 0.000 description 1
- 230000023556 desulfurization Effects 0.000 description 1
- 238000009509 drug development Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 201000004101 esophageal cancer Diseases 0.000 description 1
- 238000002290 gas chromatography-mass spectrometry Methods 0.000 description 1
- 201000010536 head and neck cancer Diseases 0.000 description 1
- 208000014829 head and neck neoplasm Diseases 0.000 description 1
- 230000002363 herbicidal effect Effects 0.000 description 1
- 239000004009 herbicide Substances 0.000 description 1
- 231100000086 high toxicity Toxicity 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000012417 linear regression Methods 0.000 description 1
- 208000006132 lipodystrophy Diseases 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- KPUREKXXPHOJQT-UHFFFAOYSA-N mesotrione Chemical compound [O-][N+](=O)C1=CC(S(=O)(=O)C)=CC=C1C(=O)C1C(=O)CCCC1=O KPUREKXXPHOJQT-UHFFFAOYSA-N 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 230000008558 metabolic pathway by substance Effects 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 239000002899 monoamine oxidase inhibitor Substances 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 230000000361 pesticidal effect Effects 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- RZJQGNCSTQAWON-UHFFFAOYSA-N rofecoxib Chemical compound C1=CC(S(=O)(=O)C)=CC=C1C1=C(C=2C=CC=CC=2)C(=O)OC1 RZJQGNCSTQAWON-UHFFFAOYSA-N 0.000 description 1
- 229960000371 rofecoxib Drugs 0.000 description 1
- 239000012488 sample solution Substances 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 150000003457 sulfones Chemical class 0.000 description 1
- 150000003464 sulfur compounds Chemical class 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 201000005112 urinary bladder cancer Diseases 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C319/00—Preparation of thiols, sulfides, hydropolysulfides or polysulfides
- C07C319/14—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of sulfides
- C07C319/20—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of sulfides by reactions not involving the formation of sulfide groups
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
- A61K31/145—Amines having sulfur, e.g. thiurams (>N—C(S)—S—C(S)—N< and >N—C(S)—S—S—C(S)—N<), Sulfinylamines (—N=SO), Sulfonylamines (—N=SO2)
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/24—Antidepressants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C315/00—Preparation of sulfones; Preparation of sulfoxides
- C07C315/02—Preparation of sulfones; Preparation of sulfoxides by formation of sulfone or sulfoxide groups by oxidation of sulfides, or by formation of sulfone groups by oxidation of sulfoxides
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C317/00—Sulfones; Sulfoxides
- C07C317/26—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton
- C07C317/32—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton with sulfone or sulfoxide groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
- C07C317/34—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton with sulfone or sulfoxide groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton having sulfone or sulfoxide groups and amino groups bound to carbon atoms of six-membered aromatic rings being part of the same non-condensed ring or of a condensed ring system containing that ring
- C07C317/36—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton with sulfone or sulfoxide groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton having sulfone or sulfoxide groups and amino groups bound to carbon atoms of six-membered aromatic rings being part of the same non-condensed ring or of a condensed ring system containing that ring with the nitrogen atoms of the amino groups bound to hydrogen atoms or to carbon atoms
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
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- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Medicinal Chemistry (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Psychiatry (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Epidemiology (AREA)
- Pain & Pain Management (AREA)
- Hospice & Palliative Care (AREA)
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Abstract
The invention discloses a monoamine oxidase A inhibitor, which is obtained by catalyzing thioether synthesis at room temperature by using cheap ruthenium carbon as a catalyst, and specifically comprises the following steps: the compound shown as the formula (III) is used as a reaction raw material, Ru/C is used as a catalyst, and NaIO is added4The method is characterized in that the method is carried out at room temperature by taking water as a solvent as an oxidant, and after the reaction is finished, the reaction solution is subjected to post-treatment to obtain the sulfone compound shown in the formula (IV). According to the method, water is used as a solvent, and cheap ruthenium carbon is oxidized by sodium periodate to generate ruthenium tetroxide, so that a target product is further synthesized by oxidizing a thioether compound, and the preparation method is more efficient, quicker, environment-friendly and mild. The prepared monoamine oxidase A inhibitor has good monoamine oxidase A inhibition activity, can be used for preparing medicines for inhibiting the monoamine oxidase A activity, has wide application prospect in medicine development, and provides a more effective way for treating related diseases.
Description
(I) technical field
The invention relates to a monoamine oxidase A inhibitor, a synthesis method and application thereof.
(II) background of the invention
The sulfone compound is a very important organic synthesis intermediate, has very wide application in the aspects of medicinal chemistry, material science and wide bioactivity. For example, bicalutamide (structure a) is an anti-androgen drug, and is suitable for treating advanced prostate cancer; laropilan (structure b) is a commonly used cardiovascular drug for the treatment of lipodystrophy; rofecoxib (structure c) is a cyclooxygenase selective inhibitor, can be used for treating arthritis and relieving pain, has good patient tolerance, and also has potential clinical value and therapeutic effect in preventing carcinoma of large intestine and esophageal cancer, and treating head and neck cancer, breast cancer, bladder cancer and cervical cancer; has certain bacteriostasis effect than dapsone (structure d) and is often used for treating leprosy. Meanwhile, the sulfone compound also plays a very important role in agricultural chemicals, for example, mesotrione (structure f) is a common herbicide, and has the advantages of no influence on the environment, no influence on the pesticide effect due to rainfall and the like. Meanwhile, sulfide oxidation is the basis of catalytic oxidative desulfurization of crude oil, wherein sulfur compounds are removed, which is also one of the most common difficulties.
Ruthenium tetroxide has been widely used in oxidation reactions since Djerassi reported in 1953 as an oxidant for use in chemical reactions. However, ruthenium tetroxide has the disadvantages of unstable property, high toxicity, high price and the like, which has certain limitations on chemical research. Therefore, it becomes crucial to find a more green, inexpensive, versatile, highly selective process. The method uses sodium periodate to oxidize cheap ruthenium carbon to generate ruthenium tetroxide, thereby further oxidizing the thioether compound to synthesize the sulfone compound.
Monoamine oxidase is a main enzyme participating in monoamine substance metabolism in vivo, monoamine oxidase is divided into A type and B type, metabolic substrates of monoamine oxidase are different, monoamine oxidase activity has a certain relation with body aging and Parkinson's disease, and monoamine oxidase inhibitor is used for treating various diseases which have proved to have obvious effects, such as depression, Parkinson's disease, senile dementia and the like.
Disclosure of the invention
The present invention provides a monoamine oxidase A inhibitor obtained by catalyzing thioether synthesis at room temperature using inexpensive ruthenium carbon as a catalyst. The monoamine oxidase A inhibitor has extremely strong monoamine oxidase A inhibition effect, and is applied to preparation of drugs for inhibiting monoamine oxidase A activity.
The technical scheme of the invention is as follows:
a monoamine oxidase A inhibitor of formula (IV) synthesized as follows:
the compound shown as the formula (III) is used as a reaction raw material, Ru/C is used as a catalyst, and NaIO is added4The method comprises the following steps of (1) reacting at room temperature (20-30 ℃) by taking water as a solvent as an oxidant, and after the reaction is finished, carrying out post-treatment on a reaction solution to obtain a sulfone compound shown as a formula (IV); the amount of the Ru/C is 0.5-2%, preferably 1%, of the amount of the substance of the compound shown in the formula (III) in terms of the amount of the substance of Ru; the NaIO4The amount of the substance(s) is 50 to 150%, preferably 110% of the amount of the substance of the compound represented by the formula (III).
Further, the volume usage amount of the water is 3-5 mL/mmol based on the amount of the compound shown in the formula (III).
The progress of the reaction of the present invention can be monitored by a conventional method, for example, TLC is used to monitor the completion of the reaction of the starting compound represented by formula (III) to determine the time point of the completion of the reaction; the reaction time is usually 2-3 h.
Further, the post-treatment method of the reaction solution comprises the following steps: after the reaction is finished, the reaction solution is filtered, washed by dichloromethane, the filtrate and the washing solution are combined, washed twice by saturated sodium chloride solution, and dehydrated by anhydrous sodium sulfate, the solvent is removed by evaporation and dried, and the target product shown in the formula (IV) is obtained.
Compared with the prior art, the invention has the beneficial effects that:
(1) the invention provides a monoamine oxidase A inhibitor, which has the advantages of simple preparation process and operation process, nearly 99% yield and simple subsequent treatment, and can obtain a pure product without complicated separation and purification.
(2) Compared with the traditional method, the method takes water as a solvent, uses sodium periodate to oxidize cheap ruthenium carbon to generate ruthenium tetroxide, further oxidizes the thioether compound to synthesize a target product, and is more efficient, quicker, more environment-friendly and milder.
(3) The monoamine oxidase A inhibitor has good monoamine oxidase A inhibition activity, can be used for preparing drugs for inhibiting the monoamine oxidase A activity, has wide application prospect in drug development, and is expected to provide a more effective way for treating related diseases.
(IV) detailed description of the preferred embodiments
The invention will be further described with reference to specific examples, but the scope of the invention is not limited thereto.
Example 1: preparation of ether compound III
The reaction formula is as follows:
1.258g (5.0mmol) of Compound II (from Sigma-Aldrich) and 1.382g (10.0mmol) of potassium carbonate were charged into a reaction flask, dissolved in 60mL of acetone, stirred, and 0.576g (5.0mmol) of Compound I (from Sigma-Aldrich) was added thereto, and the reaction was refluxed at elevated temperature for 7 hours. The completion of the reaction of compound II was checked by TLC and the reaction was stopped. The reaction solution was filtered and washed with dichloromethane (50 mL. times.2), and the filtrate and the washings were combined. Washing twice with saturated sodium chloride solution, drying with anhydrous sodium sulfate, evaporating to remove solvent, and separating by column chromatography (mobile phase n-hexane: ethyl acetate: 15: 1) to obtain refined compound III with yield of 77%. The structure of the compound of formula III is characterized as follows:
1H NMR(500MHz,CDCl3)δ7.71-7.25(m,3H),4.28(s,1H),3.79-3.75(m,2H),3.23-3.18(m,2H),3.94-3.61(m,4H),3.17(s,1H),2.47(s,3H).13C NMR(125MHz,CDCl3)δ136.8,133.4,133.2,129.9,128.0,126.4,77.3,73.8,48.9,51.3,32.6,23.4,14.7.GC-MS(EI):m/z285.04[M+].
example 2: preparation of sulfones compound IV
The reaction formula is as follows:
to a reaction flask were added 0.02g of Ru/C catalyst, 470mg (2.2mmol) of sodium periodate, and 4mL of water, and then 285mg (1mmol) of compound III was added to the reaction flask with stirring and reacted at room temperature for 2 hours. The completion of the reaction of the compound III was checked by TLC and the reaction was stopped. The reaction solution was filtered, washed with dichloromethane (15 mL. times.2), and the filtrate and the washings were combined. The reaction mixture was washed twice with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and the solvent was evaporated to give compound IV in 99% yield. The structure of the compound of formula IV is characterized as follows:
1H NMR(500MHz,CDCl3)δ8.29-7.60(m,3H),4.27(s,1H),4.20-4.17(m,2H),3.92-3.88(m,2H),3.56-3.53(m,2H),3.27-3.24(m,2H),3.19(s,1H),3.34(s,3H).13C NMR(125MHz,CDCl3)δ141.7,138.9,134.5,131.0,128.3,126.8,81.5,74.1,57.0,51.4,50.2,47.9,39.5.HRMS(ESI):C13H17ClNO4S2 +for[M+H]+,calculated 350.0282,found350.0277.
example 3: monoamine oxidase A inhibitory Activity test
(1) Sample preparation
The compound (IV) prepared in example 2 was dissolved in dimethyl sulfoxide (DMSO) to prepare sample solutions having concentration gradients of 5, 15, 25, 35, 45, 60, 75, 90, 105, and 120mmol/L, respectively, which was designated as sample 1.
(2) Method for testing and detecting monoamine oxidase-A inhibitory activity of compound (IV)
To an EP tube containing 386 μ L of A boric acid buffer solution (pH 8.4), 4 μ L of monoamine oxidase-A (MAO-A) and 4 μ L of sample 1 prepared in step (1) were added, respectively, mixed, and the mixture was reacted in A water bath at 38 ℃ for 2 hours, and then to the above EP tube, 2 μ L of probe 7- (3-aminopropoxy) -4-methylcoumarin (10mmol/ml) represented by formulA (V) and 4 μ L of bovine serum albumin (bsA) were added, respectively, and the reaction was continued in A water bath at 38 ℃ for 2 hours. Simultaneously with this, the enzyme activity of the enzyme without inhibitor was measured by adding 4. mu.L of monoamine oxidase-A (MAO-A) to an EP tube containing 390. mu.L of boric acid buffer (pH 8.4), reacting in A38 ℃ water bath for 2 hours, and then adding 2. mu.L of probe (10mmol/ml) and 4. mu.L of BSA, and reacting in A38 ℃ water bath for 2 hours.
Finally, 100. mu.L of each EP tube (microcentrifuge tube) was placed in a 96-well plate and the sample was examined with a full-function spectrofluorometer (. lamda.ex/. lamda.em. 365/460nm) (spectraMax M, molecular instruments, USA). Calculating the IC of sample 1 from the measured fluorescence values50The results of the test for inhibition of monoamine oxidase-A activity by Compound (IV) are shown in Table 1.
Half Inhibitory Concentration (IC) for inhibitory effect of Compound50) To indicate. IC (integrated circuit)50This is the concentration of inhibitor at which the "response" is inhibited by half, the greater the inhibitory potency of the compound, the lower the value.
IC50Can be calculated in the following way:
1) the average fluorescence intensity (F) of the enzyme-and-probe-only buffer was detected and calculatedM);
2) Calculating the fluorescence intensity of each component enzyme containing different concentration gradient inhibitors (the background value is subtracted);
3) according to the fluorescence intensity of each component enzyme of the inhibitor with different concentration gradients, linear regression of the relation between the concentration (C) and the fluorescence intensity (F) of the inhibitor is carried out, and an equation is established: f ═ aC + b (equation coefficients a and cut squat b are determined by regression lines);
4) according to the equation, F is 1/2FMThe corresponding inhibitor concentration at which the inhibition rate was 50% was determined as IC50。
Table 1 inhibitory Activity of Compound (IV) prepared in example 2 on monoamine oxidase A
Compound | MAO-A IC50(μM) |
IV | 1.079 |
As can be seen from Table 1, compound (IV) has a strong inhibitory activity against monoamine oxidase A.
Claims (7)
2. a process for the preparation of a monoamine oxidase a inhibitor of formula (IV) according to claim 1, characterized in that it comprises the following steps:
the compound shown as the formula (III) is used as a reaction raw material, Ru/C is used as a catalyst, and NaIO is added4The monoamine oxidase A inhibitor shown in formula (IV) is obtained by carrying out reaction at room temperature by using water as a solvent as an oxidant and carrying out post-treatment on a reaction solution after the reaction is finished; the dosage of the Ru/C is 0.5-2% of the dosage of the compound shown in the formula (III) in terms of the dosage of the Ru; the NaIO4The amount of the substance (B) is 50 to 150% of the amount of the substance of the compound represented by the formula (III);
3. a process for the preparation of a monoamine oxidase a inhibitor of formula (IV) according to claim 2, characterized in that: the amount of Ru/C is 1% of the amount of substance of the compound represented by the formula (III) based on the amount of substance of Ru.
4. A process for the preparation of a monoamine oxidase a inhibitor of formula (IV) according to claim 2, characterized in that: the NaIO4The amount of substance (b) is 110% of the amount of substance of the compound represented by the formula (III).
5. A process for the preparation of a monoamine oxidase a inhibitor of formula (IV) according to claim 2, characterized in that: the volume usage amount of the water is 3-5 mL/mmol based on the amount of the compound shown in the formula (III).
6. A process for the preparation of a monoamine oxidase a inhibitor of formula (IV) according to claim 2, characterized in that: the post-treatment method of the reaction solution comprises the following steps: after the reaction is finished, the reaction solution is filtered, washed by dichloromethane, the filtrate and the washing solution are combined, washed twice by saturated sodium chloride solution, and dehydrated by anhydrous sodium sulfate, the solvent is removed by evaporation and dried, and the target product shown in the formula (IV) is obtained.
7. Use of a monoamine oxidase A inhibitor according to claim 1 for the preparation of a medicament for inhibiting monoamine oxidase A activity.
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